Denysiuk L. Diagnostic significance of TP53 gene polymorphism Pro72Arg in the development and progression of primary open-angle glaucoma

Українська версія

Thesis for the degree of Candidate of Sciences (CSc)

State registration number

0417U002520

Applicant for

Specialization

  • 14.01.18 - Очні хвороби

27-06-2017

Specialized Academic Board

Д 26.613.05

Shupyk National Medical Academy of Postgraduate Education

Essay

The thesis is devoted to the problem of improving the efficiency of diagnosis, prognosis and progression of primary open-angle glaucoma by determining the diagnostic significance of gene polymorphism Pro72Arg TP53 of patients in the Ukrainian population. Scientific novelty of the results. For the first time Ukrainian population determined the diagnostic value of gene polymorphism Pro72Arg TP53 in patients with POAG. Obtained new scientific knowledge about the molecular and genetic mechanisms of development and progression of POAG. Advanced scientific information on the frequency distribution of genotypes. Found that in patients with POAG among homozygous genotypes predominated genotype Pro72Pro, who met 1.9 times more likely (p (F) = 0,042). Arg72Arg genotype frequency decreased in 1.6 times (p (F) = 0,006). Pro72Arg polymorphism was associated with the development of POAG (2 = 9,49; p (X^2) = 0,009). The risk of developing POAG Pro72Pro genotype carriers were more than twice as high (OR = 2,17; CI = 1,02-4,61). Allele polymorphism had an association with the development of POAG (X^2 = 9,09; p (X^2) = 0,003): 72Pro allele increased the availability of risk (OR = 1,79; CI = 1,24-2,60). Supplemented scientific evidence that men with increased incidence of POAG 72Pro allele and genotype Pro72Pro gene TP53 (p <0.05). Having 72Pro allele in men and women has been associated with the development of POAG, and the risk of development was increased (p <0,05). Proapoptose 72Arg allele had a pathogenic role in the development of POAG in women under the age of 60 years, the ancestral allele 72Pro - in men aged over 60 years. Developed and designed to assess the progression of POAG new indexes (IDS, IPS and IDVOT) that consistently and statistically significantly raised according to the severity of the pathological process (p <0,01). The distribution of genotypes and allele polymorphism was associated with Pro72Arg stage of POAG, namely the initial stages - with the genotype and allele Pro72Pro 72Pro and stage III-IV - proapoptose of mutant genotype and allele Arg72Arg 72Arg (p <0,05). The value of ISS was above 1.2 times and IRS - 1.6 times at Arg72Arg genotype compared with genotype Pro72Pro (p <0,05) and in carriers of the mutant allele 72Arg compared with native ancestral allele 72Pro (p <0,005 ). The highest value was ICS women to 60 years, carriers proapoptose genotype and allele Arg72Arg 72Arg. The progression of POAG goes more rapidly in the presence proapoptose 72Arg alleles in patients younger. Found that 3.5% of POAG patients were normotensive; they had ancestral genotype Pro72Pro. In primary examination and normal IOP 72Pro allele distribution and 72Arg was the same (1: 1), in hypertensive POAG more common allele 72Arg and rarer allele 72Pro. In the media and genotypes Pro72Arg Arg72Arg had higher levels of IOP and its more rapid increase (in magnitude IDVOT) as the progression of POAG. In genotype carriers Pro72Pro IDVOT was minimal compared to other genotypes and did not differ in men and women. The largest IDVOT (p <0.05) was Arg72Arg genotype carriers (especially in women over 60). The smallest growth was noted in IDVOT male genotype carriers Pro72Pro the age of 60 years. Correlation and regression analysis first showed that the most important for predicting the IRS had IOP further (highest regression coefficient beta) - POAG in early stage research, disease duration and age of the patient. Stage POAG determined at baseline genotype and disease duration, the risk of severe stage patients with genotypes Pro72Arg (p = 0.01) and Arg72Arg (p = 0.04) higher by 3.5 and 3.2 times, respectively, compared with genotype Pro72Pro. The level of IOP is inversely dependent on the age of the patient and directly - on the duration of the disease. In other standardization growth factors found (p = 0,04) higher risk of IOP in patients with genotype Arg72Arg 2.6 times compared with genotype Pro72Arg or Pro72Pro. In primary examination of patients with genotype Pro72Pro was not even with high IOP. The practical significance of the results. Results of the study allowed for the first time in the Ukrainian population to formulate criteria for the formation of risk for developing POAG. It includes media genotype and allele Pro72Pro 72Pro gene polymorphism Pro72Arg TP53. Given that the genotype does not change with age, this definition should be done as early as possible. First identified individual risk of progression of POAG women aged less than 60 years in the presence of genotype Arg72Arg (2.7 times), allele 72Arg (1.9 times) compared to older women; women aged less than 60 years, carriers have Arg72Arg genotype compared with men of the same age; men over 60 in the presence of genotype Pro72Pro (3.3 times) and allele 72Pro (1.9 times) compared with women of the same age; men over 60 years, carriers of genotype Pro72Pro (in 7.0 times) and allele 72Pro (3.6 times) compared to younger men. Developed and implemented in practice the original model of multiple regression ICS definition, which has a high predictive value. With increasing duration of disease progression POAG chances and go to the next step of growing more than 4 times per year. The chances of III-IV stages of POAG patients with genotype Pro72Arg increased 3.5 times, and for patients with genotype Arg72Arg - 3 times compared with genotype Pro72Pro. In patients with genotype Arg72Arg compared to other high-level risk genotypes IOP increases 2.6 times.

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